Apoptosis Regulated by Fibronectin Signaling Pathways

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Altered fibronectin matrices, as those elaborated during periodontal disease or inflammation compromise periodontal ligament (PDL)cell function. During the course of inflammation, bacterial and host-derived proteases cleave the extracellular matrix (ECM) and release fragments of the ECM, including fibronectin fragments, into the inflammatory milieu. We have shown that these fragments negatively influence PDL cell function by limiting their proliferative capacity and chemotaxis, and by inducing programmed cell death or apoptosis in these cells. The signaling mechanism by which this apoptosis is triggered is novel and requires the transcriptional downregulation of p53. Upstream of p53,decreases in focal adhesion kinase phosphorylation and increases in c-Jun N-terminal kinase (JNK)1 phosphorylation regulate this pathway. Furthermore, JNK1 and JNK2 oppositely regulate p53 levels in this process, however, the mechanism by which this occurs is not known. Yet, understanding this mechanism is critical to understanding how the stress-related condition of an altered fibronectin matrix environment regulates p53 and how p53 is regulated in general. Reports have shown that JNK phoshorylation of p53 can stabilize p53 and modulate its transcriptional activity. Conversely, JNK targets p53 for ubiquitination and proteasomal degradation in an Mdm-2 independent manner in nonstressed conditions. We hypothesize that JNK1 and JNK2 oppositely regulate p53 and apoptosis under altered fibronectin matrix conditions by modulating p53 at a transcriptional level and by ubiquitination and proteasomal degradation, independent of Mdm-2. Thus, the mechanism by which JNK1 and JNK2 oppositely regulate p53 and apoptosis under altered fibronectin matrix conditions will be examined in this study. This study will expand our understanding of the intricate mechanisms that tightly regulate p53,a key regulator of apoptosis, and of the specific modulation of p53 and apoptosis by stress-activated kinases,JNK1 and JNK2 under altered fibronectin matrix conditions which relate to periodontitis.